The long-term objective of my plan for this award is to develop interventional studies targeting the molecular-genetic mechanisms of cancer-related fatigue identified in my initial study and to determine their role in mitigating symptoms. My career goal is to become an independent investigator, developing and conducting translational research linking insights from basic science, behavioral research, and clinical practice in the area of cancer symptom management. To that end, the K01 award will enable me to obtain essential training in advanced biomedical research, particularly related to bioenergetics. Under the mentorship of experienced research faculty, this will lead to competitive research proposals integrating bench science, clinical practice, and novel interventions, using a molecular-genetics perspective on symptom management in cancer. Specific Training Objectives: Objective 1. Obtain required in-depth understanding in biochemistry, molecular biology, and mitochondrial metabolism. Objective 2. Develop skills in laboratory measurement of mitochondrial bioenergetics. Objective 3. Optimize and tailor standard laboratory procedures to the use of human lymphocytes in order to test proposed hypotheses. Objective 4. Acquire understanding of the relationships among gene expression, mitochondrial bioenergetics, and patient symptom experience (i.e., fatigue). Objective 5. Improve scientific communication skills required to coordinate laboratory investigation and clinical research. Objective 6. Collaborate with senior investigators to gain experience in leading translational and multidisciplinary research projects. The ultimate purpose of this program of research is to develop and test interventions to improve healthrelated quality of life for prostate cancer patients, specifically targeting fatigue-one of te most common and distressing sequelae of localized radiation therapy (XRT) for cancer. Cancer-related fatigue negatively impacts health outcomes, leading to increased depression, impaired cognitive function, increased sleep disturbance, and decreased health-related quality of life. The physiological mechanisms behind fatigue and its increased severity during localized XRT remain unknown. Although many mechanisms have been proposed for cancerrelated fatigue, the elusiveness of its cause presents barriers to effective management. A reduction in the capacity of neutrophil mitochondria to utilize oxygen and synthesize adenosine triphosphate (ATP) has been associated with chronic fatigue syndrome. Based on our preliminary data and the literature, localized radiation induces damage to cellular processes, alters gene expression (downregulated BCS1L and upregulated SLC25A37), and is accompanied by decreased BCS1L protein and increased mitoferrin-1 protein. Our primary hypothesis is that decreased BCS1L leads to a defect in complex III assembly and activity, causes impaired oxidative phosphorylation (OXPHOS), and results in decreased ATP production that contributes to the fatigue suffered by cancer patients receiving localized XRT. Moreover, the defect in complex III iron-sulfur protein leads to increased electron leakage from complex III and increased production of superoxide. Our hypothesis provides a mechanism for impaired ATP production as a major consequence of XRT that leads to debilitating radiation-induced fatigue. Furthermore, increased reactive oxygen species (ROS) exacerbates the mitochondrial and cellular damage, adding to the pathophysiology of cancer-related fatigue. Specific Research Aims: Aim 1: To quantify the expression of BCS1L and SLC25A37 associated with changes of BCS1L and SLC25A37 protein in lymphocytes from prostate cancer patients with XRT, compared to prostate cancer patients undergoing active surveillance (AS), at baseline, midpoint, and endpoint. Aim 2: To determine mitochondrial bioenergetics profile for prostate cancer patients with XRT compared to those for prostate cancer patients under AS, at baseline, midpoint, and endpoint. 2a. Determine the rate of mitochondrial OXPHOS, especially complex III. 2b. Measure the activity of electron transport chain (ETC) complexes, especially complex III. 2c. Determine the content of ETC complexes, especially complex III. 2d. Measure the amount of ATP and ROS production. Aim 3: To determine the associations among changes in fatigue, changes in the expression of BCS1L and SLC25A37, and changes in the mitochondrial bioenergetics of prostate cancer patients with XRT and AS. 3a. Measure the severity of fatigue at baseline, midpoint, and endpoint for XRT and AS groups. 3b. Determine the associations of changes in fatigue with changes in the expression of BCS1L and SLC25A37, and changes in the mitochondrial bioenergetics over time in XRT and AS groups.